Immunomodulatory oligonucleotides

Abstract

Oligonucleotides containing unthylated CpG dinucleotides and therapeutic utilities based on their ability to stimulate an immune response in a subject are disclosed. Also disclosed are therapies for treating diseases associated with immune system activation that are initiated by unthylated CpG dinucleotides in a subject comprising administering to the subject oligonucleotides that do not contain unmethylated CpG sequences (i.e. methylated CpG sequences or no CpG sequence) to outcompete unmethylated CpG nucleic acids for binding. Further disclosed are methylated CpG containing dinucleotides for use antisense therapies or as in vivo hybridization probes, and immunoinhibitory oligonucleotides for use as antiviral therapeutics.

The invention claimed is: 
     
       1. A method of inducing an antigen-specific immune response in a subject comprising: administering a vaccine to a human subject wherein the vaccine includes an antigen in combination with an immunostimulatory oligonucleotide of 8 to 40 nucleotides in length, comprising:
 5′X1X2CGX3X43′, wherein C and G are unmethylated and X1, X2, X3, and X4 are nucleotides, in an amount effective to induce the antigen-specific immune response. 
 
     
     
       2. A method of inducing an antigen-specific immune response in a subject comprising: administering a vaccine to a human subject wherein the vaccine includes an antigen in combination with an immunostimulatory oligonucleotide of 8 to 40 nucleotides in length, comprising:
 5′X1X2CGX3X43′, wherein C and G are unmethylated and X1, X2, X3, and X4 are nucleotides, 
 wherein the immunostimulatory oligonucleotide does not include a GCG trinucleotide at a  5 ′ and/or 3′ terminal, in an amount effective to induce the antigen-specific immune response. 
 
     
     
       3. A method of inducing an antigen-specific immune response in a subject comprising: administering a vaccine to a human subject wherein the vaccine includes an antigen in combination with an immunostimulatory oligonucleotide of 8 to 40 nucleotides in length, comprising:
 5′X1X2CGX3X43′, wherein C and G are unmethylated and X1, X2, X3, and X4 are nucleotides, 
 wherein the immunostimulatory oligonucleotide does not contain a 5′X1X2CGX3X43′ palindrome, in an amount effective to induce the antigen-specific immune response. 
 
     
     
       4. A method of inducing an antigen-specific immune response in a subject comprising: administering a vaccine to a human subject wherein the vaccine includes an antigen in combination with an immunostimulatory oligonucleotide of 8 to 40 nucleotides in length, comprising:
 5′X1X2CGX3X43′, wherein C and G are unmethylated and X1, X2, X3, and X4 are nucleotides, 
 wherein the immunostimulatory oligonucleotide does not include a GCG trinucleotide at a 5′ and/or 3′ terminal, wherein the immunostimulatory oligonucleotide does not contain a 5′X1X2CGX3X43′ palindrome, in an amount effective to induce the antigen-specific immune response. 
 
     
     
       5. The method of  claim 1 , wherein the immunostimulatory oligonucleotide includes a phosphate backbone modification that is a phosphorothioate. 
     
     
       6. The method of  claim 1 , wherein the immunostimulatory oligonucleotide is administered orally. 
     
     
       7. The method of  claim 1 , wherein the immunostimulatory oligonucleotide is administered by injection. 
     
     
       8. The method of  claim 1 , wherein the immunostimulatory oligonucleotide is administered transdermally. 
     
     
       9. The method of  claim 1 , wherein the immunostimulatory oligonucleotide is in a pharmaceutically acceptable carrier. 
     
     
       10. The method of  claim 1 , wherein the immunostimulatory oligonucleotide includes at least two unmethylated cytosine-guanine motifs.